Sister chromatids are preferred substrates for the recombinational repair of DNA lesions. Sister chromatid recombination (SCR) results in the exchange of genetic information between newly replicated chromatids and ensures that DNA lesions are either tolerated or repaired. Faulty recombinational repair has been correlated to several genetic diseases, including Blooms syndrome, inheritable breast cancer (BRCA1 and BRCA2), and Fanconis Anemia. One approach to understand SCR mechanisms is to clarify the SCR phenotypes in mutants defective in well-conserved radiation repair (RAD) genes. These RAD genes include those that participate directly in the recombinational repair of double-strand breaks (DSBs), known as the RAD51 subgroup, and those that participate in the processing of the DNA break, known as the RAD50 subgroup. A systematic analysis of SCR recombination phenotypes in rad mutants revealed multiple pathways for spontaneous and DNA damage-associated SCR in yeast. Studies focused on vertebrate RAD51 genes have suggested similar pathways. In this review, we shall discuss methods for detecting SCR, recombinatio n mechanisms that generate SCR, mammalian and yeast genes that participate in SCR, and genetic diseases characterized by SCR phenotypes.